The Promise of CRISPR

In the 1990s there was a great deal of legitimate hope that antioxidant therapy would treat and perhaps even cure a long list of degenerative diseases. Oxygen free radicals damage cells, and antioxidants scavenge those free radicals. It turned out that the system was more complex than we thought, oxygen free radicals are used by cells for immune activity and metabolic signaling, and improving a complex system that evolution has already had millions of years to tinker with is not so easy.

Also at that time retroviral gene therapy promised to cure a long list of genetic diseases. The idea is clever – use the machinery of viruses to insert bits of DNA into a patient to fix a broken gene. This strategy actually works, however researchers ran into safety problems. The viral vectors can sometimes become replication competent, meaning that they can reproduce and cause a serious infection. Later vectors reduced this risk, but then another risk appeared – activation of oncogenes leading to leukemia. These safety hurdles have kept this treatment from becoming widespread for the last two decades.

Around the turn of the millennia two other scientific breakthrough were heralded with much promise. The first was the Human Genome Project. Sequencing all the genes in the human genome was promised to lead to cures for many diseases. At the same time the science of stem cells was grabbing a great deal of public attention. There was an ethical controversy over harvesting fetal or embryonic stem cells, vs the promise of curing diseases like Alzheimer’s and Parkinson’s disease. Again we are approaching two decades later, stem cell research has continued to advance, yet the promise of this technology is still far in the future.

The point of reviewing this recent history is not to denigrate these important advances or the quality of the science. These are all cutting edge scientific advancements that do contain significant promise for curing diseases. The feature they share in common is that the initial hype when they first come to public attention dramatically overestimates current progress while ignoring or underestimating the difficulty and unpredictability of such cutting edge technology. These are advances that are likely to take 30-50 years to develop, and it is highly likely that we will run into obstacles that need to be solved prior to implementation.

CRISPR

With that history in mind, the latest superstar technology being hyped for its incredible promise is CRISPR – Clustered Regularly Interspaced Short Palindromic Repeats. This is a system adapted from bacteria that use it as part of their resistance against viruses. The technology allows for precise insertion of bits of DNA into the genome of an organism.

Part of the hype of CRISPR stems not only from the fact that it can precisely insert DNA where desired but also because it is a relatively cheap and easy system for a lab to use. This could allow for a massive proliferation of gene editing for research, genetic modification, and therapy.

The usual promises of gene therapy are being trotted out – curing all the horrible genetic diseases that plague humanity. How does the current hype surrounding CRISPR hold up to reality? Will we be looking back after 20 years and wondering what happened to all the promises of CRISPR scientists?

It’s too early to tell, and it could honestly go both ways, but there is no reason to assume that CRISPR will not live up to the hype. One difference that might put CRISPR into a different category is the fact that it is relatively cheap and easy, allowing for many researchers to tinker with it. Advances in CRISPR technology are happening fast.

Also on the hopeful side is the fact that CRISPR does not involve something inherently dangerous like a virus that we are hoping will not cause a deadly infection, or stem cells that like to form tumors. There is also no question that the technology works.

There is reason for caution, however. Gene editing itself is inherently dangerous. Just like with retroviral therapy, CRISPR could cause unwanted changes to the genome, such as activating genes that cause cancer. Earlier this year a paper caused a stir when they claimed to find hundreds of unintended mutations in mice treated with CRISPR. These findings were especially concerning because the mutations were in parts of the genome not thought to be at risk, and often not surveyed during CRISPR research.

However, the paper has come under considerable criticism. Nature, who published the original article, has now posted this disclaimer:

Multiple groups have questioned the interpretation that single nucleotide changes seen in whole-genome sequences of two CRISPR–Cas9-treated mice are due to the CRISPR treatment. Since the background genetic variation between the control mouse and the CRISPR-treated animals is not known, an alternative proposed interpretation is that the observed changes are due to normal genetic variation.

Even if this one study is fatally flawed, that does not end concerns about off-target mutations resulting from CRISPR. A different study published in June of 2017 warns:

An unintended consequence, however, is that sgRNA can introduce double-stranded breaks at non-targeted sites within the genome. The potential for these off-target effects are well known; thus, procedures are in place to reduce their frequency, screen for their occurrence, and in the case of sexually reproducing organisms, perform outcrossings for their exclusion from lines with the desired mutation.

The science of CRISPR is moving fast, faster than any similar technology in my memory. This raises the stakes for both the possible benefits and risks. Researchers are already moving on to human trials – there are 20 human trials involving CRISPR beginning this year (mostly in China). They include a trial to use CRISPR to prevent the human papilloma virus from causing cervical cancer. There are also trials looking at treating cancers by switching on an immune activation protein that was turned off as part of the development of the cancer (allowing it to evade the immune system).

It may also be possible to cure genetic diseases in embryos before they are implanted as part of in-vitro fertilization (IVF). Current studies are promising but also show that we are not there yet.

The future of CRISPR

Just because recent cutting edge medical technologies have turned out to be much more difficult than initially hoped, that does not mean that CRISPR will not meet or exceed expectations. It is, however, a reminder that hype needs to be tempered with caution.

CRISPR is an amazingly powerful technology, and all the hype about its potential to cure genetic diseases, fight cancer, genetically modify organisms, and aid in genetics research are actually reasonable and well-founded. However, we also have to remember that organisms are complex machines, and genetics are also horrifically complex.

So while the technology itself works and continues to advance rapidly, that applications of that technology, especially in humans, are going to take time to carefully research. There are clear safety issues, and there is the possibility of unintended consequences. These are all solvable issues, but we need to proceed with care. So far it seems that we are.

We also need to be patient. I suspect CRISPR will deliver on much of its promise, and perhaps more quickly than most similar new technologies, but that is still likely to take longer than the public’s attention span. For now we have to wait and see how the research pans out.

Posted by Steven Novella

Founder and currently Executive Editor of Science-Based Medicine Steven Novella, MD is an academic clinical neurologist at the Yale University School of Medicine. He is also the president and co-founder of the New England Skeptical Society, the host and producer of the popular weekly science podcast, The Skeptics’ Guide to the Universe, and the author of the NeuroLogicaBlog, a daily blog that covers news and issues in neuroscience, but also general science, scientific skepticism, philosophy of science, critical thinking, and the intersection of science with the media and society. Dr. Novella also contributes every Sunday to The Rogues Gallery, the official blog of the SGU.